title: Colitis and colon cancer in WASP-deficient mice require helicobacter species.
abstract: BACKGROUND
  Wiskott-Aldrich syndrome protein-deficient patients and mice are immunodeficient and can develop inflammatory bowel disease. The intestinal microbiome is critical to the development of colitis in most animal models, in which Helicobacter spp. have been implicated in disease pathogenesis. We sought to determine the role of Helicobacter spp. in colitis development in Wiskott-Aldrich syndrome protein-deficient (WKO) mice.
  
  
  METHODS
  Feces from WKO mice raised under specific pathogen-free conditions were evaluated for the presence of Helicobacter spp., after which a subset of mice were rederived in Helicobacter spp.-free conditions. Helicobacter spp.-free WKO animals were subsequently infected with Helicobacter bilis.
  
  
  RESULTS
  Helicobacter spp. were detected in feces from WKO mice. After rederivation in Helicobacter spp.-free conditions, WKO mice did not develop spontaneous colitis but were susceptible to radiation-induced colitis. Moreover, a T-cell transfer model of colitis dependent on Wiskott-Aldrich syndrome protein-deficient innate immune cells also required Helicobacter spp. colonization. Helicobacter bilis infection of rederived WKO mice led to typhlitis and colitis. Most notably, several H. bilis-infected animals developed dysplasia with 10% demonstrating colon carcinoma, which was not observed in uninfected controls.
  
  
  CONCLUSIONS
  Spontaneous and T-cell transfer, but not radiation-induced, colitis in WKO mice is dependent on the presence of Helicobacter spp. Furthermore, H. bilis infection is sufficient to induce typhlocolitis and colon cancer in Helicobacter spp.-free WKO mice. This animal model of a human immunodeficiency with chronic colitis and increased risk of colon cancer parallels what is seen in human colitis and implicates specific microbial constituents in promoting immune dysregulation in the intestinal mucosa.
authors.affiliation: Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02139, USA.
authors.forename: Deanna D
authors.initials: DD
authors.lastname: Nguyen
authors.forename: Suresh
authors.initials: S
authors.lastname: Muthupalani
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Goettel
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Eston
authors.forename: Melissa
authors.initials: M
authors.lastname: Mobley
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Taylor
authors.forename: Amanda
authors.initials: A
authors.lastname: McCabe
authors.forename: Romela
authors.initials: R
authors.lastname: Marin
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
mesh_terms: D000818:Animals; D003092:Colitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004279:DNA, Viral / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D016998:Helicobacter / Q000145:classification / Q000235:genetics / Q000472:pathogenicity; D016481:Helicobacter Infections / Q000150:complications* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D014916:Whole-Body Irradiation; D051316:Wiskott-Aldrich Syndrome Protein / Q000502:physiology*
chemical_list: D004279:DNA, Viral; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein